Inflammatory bowel disease (IBD) affects about 0.5% of the world's population. Due to its early onset and lack of adequate cure, it requires lifelong treatment. IBD impacts the gastrointestinal (GI) tract and manifests as two subtypes: Crohn's disease (CD) and ulcerative colitis (UC). In recent years, anti-TNF biological agents have revolutionized the treatment of IBD, but these are not ideal drugs, requiring administration by injection, and in some instances hospitalization for intravenous infusion. They have numerous systemically-driven side effects including increased infections and anywhere from 80-95% of patients either don't respond or lose response. Hence new therapeutic options to treat IBD are needed. In this respect, the recent identification of the IL-23 pathway in chronic intestinal inflammation raises exciting new possibilities. Ustekinemab targets both the IL-12 and IL-23 pathway and is efficacious in anti-TNF-resistant IBD patients. However there is some concern of increased cardiovascular and cancer events as illustrated by the safety warning label on Ustekinumab and the removal of Briakinumab (also targeting IL-12 and IL-23). These safety concerns are thought to be due to blocking the role of IL-12 in host defense and cancer suppression, whilst blocking IL-23 signaling results in the observed efficacy. IL-23 is produced locally in the intestine and the upregulation of IL-23 and its receptor is a primary step underpinning intestinal inflammation. Since IBD represents a local inflammation of the intestinal tissue, an ideal therapeutic would act from the luminal side to achieve high drug concentrations in diseased tissue (enhanced efficacy) whilst minimizing systemic bioavailability (enhanced safety). We have obtained exciting proof-of-concept data on the oral delivery of GI-restricted drugs that are efficacious in a rodent model of disease. These IL-23R antagonists are resistant to the proteolytic and reductive environment of the gastrointestinal tract, resulting in high drug levels in diseased intestinal tissues after oral delivery and limited drug concentrations in the circulation This has the potential to transform the treatment paradigm for IBD, by providing safe, efficacious and durable drugs for life-time treatment. In this Phase I proposal we plan to: 1) Optimize the oral stability of PN738 (a 1nM antagonist) and optimize the potency of PN740, an orally stable though modestly potent (7nM) antagonist, 2) Optimize intestinal and colonic tissue exposure of orally delivered leads and 3) Evaluate efficacy of potent, orally stable IL-23R antagonists in rodent models of disease. This Phase I program is supported by a team that has a track record in the oral delivery of constrained peptides, the proven capacity in translating early stage research to clinical outcomes, a group of scientific and clinical advisors with significant experience in IBD, and the appropriate research environment. In addition, all of the required methods are in place. Phase II of the project will involve the evaluation and further optimization of lead candidates in disease models and eventual selection of Investigational New Drug candidates.